TABLE 2.
Overview of included randomized controlled trials contributing data for vitamin D intake requirement modeling
| First author, y (reference) | Country | Mean age (range) at baseline | Intervention description (dose)1 | Follow-up | Adherence/compliance2 | Vitamin D intake estimation | 25OHD assay | Sun exposure | Skin pigmentation |
|---|---|---|---|---|---|---|---|---|---|
| Aglipay et al., 2017 [30] | Canada | 2.7 y (1–5 y) | Daily child vitamin D3 supplementation (10 or 50 μg/d) | 4 mo | 100% and 98% | Estimated from study in similar population [59] | Protein-binding assay | Low (43°N; trial during winter; 35–60 min unstructured free play outdoors per week at baseline) | Multiple (Fitzpatrick skin type 13% I, 31% II, 33% III, 11% IV, 6% V, 4% VI) |
| Ala-Houhala, 1985 [31] | Finland | Birth | Daily child vitamin D supplementation (10 or 25 μg/d) | 8, 20 wk | NR | Estimated from breast milk concentration [60] and intake [14] | Competitive protein-binding assay | Variable (61°N; groups in winter and summer) | Light (largely fair skin color) |
| Ala-Houhala et al., 1986 [32] | Finland | Birth | Daily child vitamin D3 supplementation (0 or 10 μg/d) for 15 wk | 8, 15 wk | NR | Estimated from breast milk concentration [60] and intake [14] | Competitive protein-binding assay | Low (61°N; recruited in January) | Light (largely fair skin color) |
| Alonso et al., 2011 [33] | Spain | 1 mo | Daily child vitamin D3 supplementation (0 or 10 μg/d) | 3, 6, 12 mo | Excluded noncompliant | Estimated from study in similar population [61] | EIA/Chemiluminescence | Variable (43°N; recruited over 1 y; excluded children with sunlight exclusion) | Light/medium (excluded dark skin pigmentation) |
| Atas et al., 2013 [34] | Turkey | 15 d | Daily child vitamin D3 supplementation (5 or 10 μg/d) | 4 mo | Excluded infants lost to follow-up and improper vitamin D supplementation | Estimated from breast milk concentration [13] and intake [14] | HPLC | Variable (40.6°N; recruited over 1 y) | Probably medium (Middle East) |
| Chan, 1982 [35] | United States | 2 wk | Human milk with daily maternal supplementation (vitamin D 10 μg/d and calcium 250 mg/d) or human milk with daily child vitamin D supplementation (10 μg/d) or vitamin D-fortified formula (vitamin D 10 μg/L, calcium 0.51 mg/dL and phosphorus 0.39 mg/dL)) | 2, 4, 6 mo | NR | Reported in the study and combined with estimates from breast milk concentration [13] and intake [14] | Competitive protein-binding assay | Probably low (40.8°N; no seasonal variation was found in the study) | Light (Caucasian) |
| Chandy et al., 2016 [36] | India | 2–4 d | Daily child vitamin D3 supplementation (0 or 10 μg/d) | 3.5 mo | 94% | Estimated from breast milk concentration [13] and intake [14] | RIA kits | Probably significant (26°N; mothers were instructed to give infant massage under the sun 15 min/d) | Probably medium (India) |
| Enlund-Cerullo et al., 2019 [37] | Finland | 2 wk | Daily child vitamin D3 supplementation (10 or 30 μg/d) | 12, 24 mo | 89% and 87% | Estimated from study in similar population [62] | EIA/Chemiluminescence3 | Probably variable (60.1°N; recruited over several times of the year) | Probably light (mothers of Northern European origin) |
| Gallo et al., 2013a [38] | Canada | 1 mo | Daily child vitamin D2 or D3 supplementation (10 μg/d) | 3 mo | 89% | Estimated from study in similar population [39] | LC-MS/MS3,4 | Probably variable (45.5°N; recruited over >1 y; 58% infants born during vitamin D-synthesizing period April-October) | Multiple (67% self-identified as White, skin color based on individual topical angle: 10% very fair, 46% fair, 35% medium, 6% olive, 4% dark) |
| Gallo et al., 2013b [39] | Canada | 1 mo | Daily child vitamin D3 supplementation (10, 20, 30, or 40 μg/d) for 12 mo | 1, 2, 5, 8, 11 mo | 84–93% | Reported in the study | LC-MS/MS3,4 | Probably variable (45.5°N; recruited over >1 y; 60% infants born during vitamin D-synthesizing period April-October; sun exposure did not differ between groups, but infant sun index increased from 7 at 1 mo to 71 at 9 mo old) | Multiple (84% White) |
| Gordon et al., 2008 [25] | United States | 10 mo (8–24 mo) | Daily child vitamin D2 or D3 supplementation (vitamin D2 50 μg/d or vitamin D3 50 μg/d, both groups received calcium 50 mg/kg/d) | 6 wk | NR | Estimated from study in similar population [63] | EIA/Chemiluminescence | Probably variable (42°N; recruited over the year) | Multiple (skin pigmentation 1 (heaviest) 62%, 2 27%, 3 4%, 4 (lightest) 8%) |
| Grant et al., 2014 [40] | New Zealand | Birth | Daily child vitamin D3 supplementation (placebo 0 μg/d) for 6 mo | 2, 4, 6 mo | 78–90% | Estimated from study in similar population [39] | LC-MS/MS3 | Probably variable (36°S; recruited at all times of the year; mean time spent outdoors 0.21 h/d at 2 mo, 0.25 h/d at 4 mo, and 0.40 h/d at 6 mo) | Multiple (Mother 38% European, 24% Maori, 46% Pacific, 25% Other) |
| Greer et al., 1982 [41] | United States | 3 wk | Daily child vitamin D supplementation (0 or 10 μg/d) | 3, 9, 23 wk | 80% | Estimated from breast milk concentration [13] and intake [14] | Competitive protein-binding assay | Probably variable (43°N; unclear season; sunshine exposure 35 min/d) | Light/medium (94% Caucasian, 6% Asian-Indian) |
| Hollis et al., 2015 [42] | United States | 5 wk (4–6 wk) | Daily child and maternal vitamin D3 supplementation (10/10 μg/d) | 3, 6 mo | NR | Estimated from breast milk concentration [13] and intake [14] | RIA kits | Probably variable (38°N; recruited over different times of the year) | Multiple (59% White, 22% Hispanic, 19% Black/African American |
| Holst-Gemeiner et al., 1978 [43] | Austria | 1 wk (2–10 d) | Daily child vitamin D3 supplementation (30 μg/d) | 2, 4–6 wk | NR | Estimated from breast milk concentration [13] and intake [14] | RIA | Probably low (48°N; newborns) | Probably light (Western Europe) |
| Huynh et al., 2017 [44] | Australia | Birth | Daily child vitamin D3 supplementation (10 μg/d) | 3–4 mo | 69% | Estimated from breast milk concentration [13] and intake [14] | EIA/Chemiluminescence | Probably low (38°S; considered minimal by authors) | Multiple (Maternal skin pigmentation 50% light-olive, 50% dark) |
| Kunz et al., 1982 [45] | Germany | Birth | Daily child vitamin D3 supplementation (12.5 or 25 μg/d) | 6 wk | NR | Estimated from breast milk concentration [13] and intake [14] | Protein-binding assay | Probably low (48°N; season NR; newborns) | Probably light (Western Europe) |
| Madar et al., 2009 [46] | Norway | 6 wk | Daily child vitamin D2 supplementation (0/usual care or 10 μg/d) | 7 wk | 91% | Estimated from breast milk concentration [13] and intake [14] | HPLC-APCI-MS3 | Probably low (60°N; all seasons, no differences in 25OHD found between seasons) | Medium/dark (Pakistani, Turkish, or Somali) |
| Pehlivan et al., 2003 [47] | Turkey | 2 wk | Daily child vitamin D supplementation (10 or 20 μg/d) | 4 mo | NR | Estimated from the Global Dietary Database | EIA/Chemiluminescence | Probably low (40.8°N; according to authors, sunlight exposure is low due to dressing habits, low vitamin D dietary intake, and air pollution; time of year not mentioned, except for the control group; maternal vitamin D intake and dressing habits were correlated with 25OHD, correlations for infant 25OHD were NR) | Probably medium (Middle East) |
| Pittard et al., 1991 [48] | United States | Birth | Daily child vitamin D supplementation (10 or 20 μg/d) | 2, 4, 6, 8, 10, 14, 16 wk | NR | Reported in the study | Competitive protein-binding assay | Probably variable (32.8°N; time of year not mentioned) | Multiple (20% White, 80% Black) |
| Ponnapakkam et al., 2010 [49] | United States | Birth | Daily child vitamin D3 supplementation (0 or 5 μg/d from birth or starting at 2 mo) | 2, 4, 6 mo | 82% | Estimated from study in similar population [63] | EIA/Chemiluminescence | Variable (30°N; across several times of the year; differences in skin color and clothing were equally distributed between groups at randomization) | Multiple (dark skin color was distributed evenly between groups at randomization) |
| Rueter et al., 2019 [50] | Australia | <28 d | Daily child vitamin D3 supplementation (0 or 10 μg/d) | 3, 6 mo | NR | Estimated from studies in similar populations [39] | EIA/Chemiluminescence | Variable (32°S; recruitment across multiple seasons, no differences between seasons found; UV light exposure was measured in 42% of infants, was 1204 J/m2 in the vitamin D group and 815 J/m2 in the control group, was not correlated with 25OHD or season of birth) | NR |
| Shakiba et al., 2010 [51] | Iran | Birth | Daily child vitamin D3 supplementation (5 or 10 μg/d) | 6 mo | NR | Estimated from the Global Dietary Database | EIA/Chemiluminescence | Probably variable (32°N; January-September) | Probably medium (Middle East) |
| Siafarikas et al., 2011 [52] | Germany | 4–5 d | Daily child vitamin D3 supplementation (6.25 or 12.5 μg/d) | 6 wk | NR | Estimated from breast milk concentration [13] and intake [14] | RIA kits3 | Low (52.5°N; recruited during summer and winter equally; absolute UV-B exposure measured 2.5–20 J/m2) | Light (included only photo-types I and II according to Fitzpatrick and Bolognia) |
| Singh et al., 2018 [53] | India | Birth | Daily child vitamin D3 supplementation (0 or 10 μg/d) | 6 mo | NR | Estimated from breast milk concentration [13] and intake [14] | EIA/Chemiluminescence | Probably variable (29°N; January-September) | Probably medium (Southeast Asia) |
| Specker et al., 1992 [54] | China | Birth | Daily child vitamin D supplementation (2.5, 5, or 10 μg/d) | 6 mo | 96–131% | Estimated from the Global Dietary Database | EIA/Chemiluminescence | Variable (22, 30, 40, 47°N; enrolled during fall and spring) | Probably medium (North and South China) |
| Vervel et al., 1997 (Study 1) [55] | France | 1 mo | Daily child vitamin D2 supplementation (25 μg/d) with vitamin D-fortified or nonfortified formula | 1.5–2, 2.5–4 mo | NR | Reported in the study and combined with estimates from breast milk concentration [13] and intake [14] | Competitive protein-binding assay | Probably variable (49°N; measures at different times of the year) | NR |
| Vervel et al., 1997 (Study 2) [55] | France | Birth | Daily child vitamin D2 supplementation (12.5 or 25 μg/d) from mothers supplemented during pregnancy (0 or 12.5 μg/d) | 3 mo | NR | Reported in the study and combined with estimates from breast milk concentration [13] and intake [14] | Competitive protein-binding assay | Probably variable (49°N; recruited April-July) | NR |
| Wagner et al., 2006 [56] | United States | 1 mo | Daily child and maternal vitamin D3 supplementation (7.5/10 μg/d) | 4, 7 mo | ≥61% and ≥80% | Estimated from breast milk concentration [13] and intake [14] | RIA | Probably low (33°N; mothers were instructed to avoid direct sunlight exposure of their infants during the first 6 mo) | Multiple (maternal ethnicity 11% African American, 74% White, 15% Hispanic) |
| Zhou et al., 2018 [57] | China | 7.8 mo (3–12 mo) | Daily child vitamin D3 supplementation (10 or 30 μg/d) | 2, 4 mo | Excluded noncompliant | Estimated from the Global Dietary Database | NR | Variable (29°N; recruited over multiple seasons) | Probably medium (China) |
| Ziegler et al., 2014 [58] | United States | 24–32 d | Daily child vitamin D3 supplementation (5, 10, 15, or 20 μg/d) | 1, 3, 4.5, 6.5, 8, 11 mo | 103.40% | Estimated from breast milk concentration [13] and intake [14] and food intake from study in similar population [63] | RIA kits | Low (41°N; main assessment during winter, minimal sun exposure) | Multiple (90% White, 4% Hispanic, 3% African American, 2% American Indian, 1% Asian) |
Abbreviations: EIA, enzyme immunoassay; HPLC, high-performance liquid chromatography; LC-MS/MS, liquid chromatography with tandem mass spectrometry; NR, not reported; RIA, radioimmunoassay; UV, ultraviolet; 25OHD, 25-hydroxy-vitamin D; HPLC-APCI-MS, high-performance liquid chromatography atmospheric pressure chemical ionization mass spectrometry; UV-B, ultraviolet B.
1
The study arms that did not correspond to the inclusion criteria were excluded from the data analyses (i.e., weekly, monthly, single-dose vitamin D supplementation, impossible to isolate effect of vitamin D or maternal vitamin D supplementation <12.5 μg/d).
2
Expressed as a percentage of the dose taken, unless stated otherwise.
3
Participated in an external quality assessment scheme for serum 25OHD measurement.
4
Also measured serum 25OHD with immunoassay.